The compound omeprazole (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole) is well known as an effective gastric acid secretion inhibitor and is useful as an anti-ulcer agent. Omeprazole has two enantiomeric forms R-omeprazole and S-omeprazole shown below and normally exists as a racemic mixture. The S-enantiomer commonly referred to as esomeprazole is said to have improved pharmacokinetic properties which give an improved therapeutic profile such a lower degree of inter-individual variation (see WO 94/27988).

Enantiomers and their mixtures, including racemates behave identically or similarly in achiral environment in view of chemical reactivity and physical properties of liquid and gaseous state. But physico-chemical properties of solid state forms of racemates and enantiomers differ significantly and they cannot be automatically predicted from one to the other. For instance, racemic omeprazole in neutral form is well crystalline compound while neutral esomeprazole is often semisolid and needs special treatment to obtain easily insoluble and stable crystals (WO 98/28294). Consequently pharmaceutically applicable form of esomeprazole is its magnesium salt (WO 98/54171) which is better crystalline than neutral form which is the main market form of racemic omeprazole. Not easily available solid state means also lack of an efficient purification tool for purification by recrystallisation. Racemic neutral omeprazole of very high chemical purity over 99.94% can be reached in a relatively simple way (U.S. Pat. No. 6,191,148) while the purification of esomeprazole needs other approaches. One of most efficient tools is well crystalline potassium salt which is used for preparation of magnesium salt of esomeprazole in many literature sources (WO 00/44744, WO 06/001753).
Esomeprazole can be prepared by enantioselective chemical reaction or by separation of S-enantiomer from racemate. Catalytic enatioselective oxidation of prochiral sulphide was first disclosed in WO 96/02535. Relatively complex mixture of reagents in this reaction and in later published alternative approaches needs an efficient purification method in order to eliminate inorganic and organic impurities especially overoxidated sulfone. Separation of enantiomers by diastereomeric derivatives is disclosed in WO 92/08716 and WO 05/105786. Cleaving of derivatising group can produce new impurities which must be removed. Separation by chiral chromatography is also described (WO 05/105786, WO 07/071,753).
Injectable forms of omeprazoles use sodium salt due to their excellent solubility in water. Sodium salt of racemic omeprazole of high purity can be simply prepared from very pure neutral form and only care how to make the most stable physical form should be taken. Because very pure neutral form of esomeprazole is less accessible analogous procedure for esomeprazole sodium cannot be performed. Procedure from very pure potassium salt by direct reprecipitation is very suitable in preparation of magnesium salt (WO 05/105786) while such procedure fails in preparation of sodium salt due to better solubility of sodium salt. Reacidification of a salt to make a neutral intermediate should be done, but this readily reproduces new impurities, because omeprazole is unstable in acidic condition and at least colorification happens.
Esomeprazole sodium was first disclosed in WO 94/027988 preparing it from crude esomeprazole in toluene-2-butanone mixture after separating derivatized diastereoisomers and removal of derivatizing group in acidic conditions. Toluene is not very suitable solvent for the last step and the method does not guarantee removal of inorganic impurities.
WO 01/014367 describes a preparation of esomeprazole sodium in THF from crude esomeprazole after enantioselective oxidation. The solvent has similar deficiencies like toluene.
WO 03/089408, WO 04/052882 and WO 07/013,743 disclose preparation of esomeprazole sodium from methyl isobutyl ketone and tried to purify the crude material by crystallisation from acetone or digesting in acetonitrile respectively. Purities 99.8% and 85% are reached.
WO 06/001753 discloses preparation of three novel crystal forms starting from potassium salt. After acidification in order to obtain neutral esomeprazole toluene again is used. WO 06/001755 describes preparation of another new polymorph B but the procedure is not industrially applicable. It applies natural evaporation of water from extremely concentrated water solution.
Patent application US 2007/0259921 shows the first preparation of very pure esomeprazole but is silent about very pure starting neutral esomeprazole and its significance. Furthermore Form J which is the most pure form easily converts to Form K, but the interchangeability between physical forms does not guarantee a repeatable process. Other described forms are less pure.
Therefore it is still need for preparation of highly pure esomeprazole sodium by a repeatable process which guarantees stable physical form.